Abstract

Nanoscale wear particles generated over time in the implant–bone interface induce profound periprosthetic inflammatory osteolysis, the most common complication after total joint arthroplasty, while macrophages serve as key initiators of this response. Ferroptosis represents a recently identified mode of regulated cell death distinguished by its nonapoptotic nature and reliance on iron-driven lipid peroxidation, which is strongly linked to inflammatory processes within macrophages. However, the contribution of macrophage ferroptosis to the development of wear particle-induced periprosthetic osteolysis has not yet been elucidated. Here, we revealed the existence of macrophage ferroptosis in both the soft tissue from the implant–bone interface of patients with aseptic loosening and wear-particle-stimulated BMDMs, which promoted inflammatory osteolysis. Our results further suggested that wear particle-induced macrophage ferroptosis is mainly associated with GPX4-related antioxidized function impairment rather than iron metabolism alteration. Mechanistically, we found that wear particle-induced macrophage ferroptosis was mediated by inhibition of the Sirtuin 1/Nrf2/GPX4 pathway, while activation of this pathway effectively alleviates the wear particle-related periprosthetic inflammatory osteolysis. Overall, our results uncovered that wear particles drive macrophage ferroptosis via inhibiting the Sirtuin 1/NRF2/GPX4 pathway to induce periprosthetic inflammatory osteolysis and provide new insights into the intricate cellular and molecular mechanisms responsible for aseptic implant loosening.